Processes for the Preparation of Benzoimidazole Derivatives

ABSTRACT

The present invention relates to a process for preparing a compound of the formula I  
                 
 
or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof. wherein R 1 , R 2 , R 3  and R 4  are as defined herein. The compound of formula I is useful in the treatment of abnormal cell growth, such as cancer in mammals.

BACKGROUND OF THE INVENTION

This invention relates to novel processes for preparing benzimdazolederiatives that are useful in the treatment of abnormal cell growth,such as cancer, in mammals. This invention also relates to novelprocesses for preparing intermediates that may be converted to theaforementioned benzimidazole derivatives. Benzimidazole derivatives,intermediates useful in preparing such bezimidazole derivatives andprocesses for preparing such benzimidazole derivatives and intermediateshave been disclosed in Interational Patent Publication WO 01/40217published Jun. 7, 2001, and U.S. Provisional Patent Applicatton Ser.Nos. 60/406,524, and 60/417,047, filed Aug. 28, 2002, and Oct. 28, 2002respectively.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a compound ofthe formula I

or a pharmaceutically acceptable salt, prodrug, hydrate or solvatethereof; wherein each R¹, R², and R³ is independently selected from thegroup consisting of H, (C₁-C₆)alkl, (C₃-C₈) cycloalkyl, halo, cyano,CF₃difluoromethoxy, trifluoromethoxy, —O(C₁-C₆)alkyl, —O(C₃-C₈)cycloalkyl, and —NR¹²R¹³;

wherein R⁴ is —(CR⁵R⁸)_(m)H, or —(CR⁷R⁸)_(m)(4 to 10membered)-araornatic or nonaromatic beterocyclic containing one or moreheteroatoms each seleoted fom O, S and N, wherein m is an integerranging from 1 to 5, wherein n is an integer ranging from 0 to 5,wherein said 4 to 10 membered heterocyolic when aromatic is optionallysubstituted by 1 to 3 R⁸ substituents, and wherein said 4 to 10 memberedheterocyclic when non-aromatic is optionally substitled by 1 to 3 R¹⁰substituents at any position and optionally substituted by 1 to 3 R¹¹substituents at any position not adjacent to or directly attached to aheteroatom;

wherein each R⁵, R⁶, R⁷ and R⁸ is independently selected from the groupconsisting of H and (C₁-C₆)alkyl, such as methyl, ethyl, propyl, butyland pentyl;

wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl, such asmethyl, ethyl, propyl, butyl and pentyl, (C₃-C₆)cycloalkyl, halo, cyano,CF₃, difluoromethoxy, trifluoromethoxy, —O(C₁-C₆)alkyl,—O(C₃C₆)cycloalkyl, and —NR¹⁴R¹⁵,

wherein each R¹⁰ is independently selected from H, (C₁-C₁₀)alkyl, and(C₃-C₆)cycloalkyl;

wherein each R¹¹ is independently selected from halo, cyano, CF₃,difluoromethoxy, trifluoromethoxy, —O(C₁-C₆)alkyl, —O(C₃-C₆)cycloalkyl,and —NR¹⁶R¹⁷;

wherein each R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is independently selectedfrom the group consisting of H, (C₁-C₆)alkyl, and (C₃-C₆)cycloalkyl;

wherein each of the aforesaid (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,—O(C₁-C₆)alky and —O(C₃-C₆)cycloalkyl substituents wherever they occurmay optionally be independently substituted by one to three substituentsindependently selected from the group consisting of halo, cyano, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂-amino, perhalo(C₁-C₆)alkyl,perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alknyl,hydroxy, and (C₁-C₆)alkoxy, comprsing reacting a compound of the formulaII

wherein BOC is t-butoxycarbonyl, and R¹, R², R³ and R⁴ are as definedabove for the compound of formula I, with a metal alkoxide, preferablyan alkaline earth metal in the presence of water to give a compound ofthe formula I. Preferably, the water is present in an amount of aboutone equivalent (i.e., one equivalent with respect to the compound offormula II). The alkaline earth metal alkoxide is preferably an alkalineearth metal (C₁-C₆)alkoxide. The alkaline earth metal is is preferablysodium or potassium, and the (C₁-C₆)alkoxide is preferably t-butoxide,

The reaction is preferably conducted in the presence of a solvent, suchas an ether. The ether is preferably a cyclic ether, although acyrlicethers may also be used, Examples of suitable ethers include dioxane,dimetnoxynethane, diethoxymethane, tetrahydrofuran and 2-methyltetrahydrofuran, or mixtures of at least two thereof. Tetrahytrofuran,2-methyltetrahydrofuran or mixtures thereof are especially preferred.Preferably the reaction is conducted at a temperature of about 50° C. toabout 110° C., and in a more preferable embodiment at a temperature ofabout 60° C. to about 80° C.

An embodiment of the present invention refers to thoses processeswherein the 4 to 10 membered heterocyclic is a 4 to 8 memberedheterocylic, in another embodiment a 4 to 6 membered heterocyclic, inanother embodiment a 6-membered heterocyclic in another embodiment a5-membered heterocyclic and in another embodiment a 4-memberedheterocyclic. Another embodiment of the present invention refers tothoses processes wherein m is an integer from 1 to 5, in anotherembodiment 1, and in another embodiment 2. Another embodiment of thepresent invention refers to those processes wherein n is an integer from0 to 5, in another embodiment 1, and in another embodiment 2. Anotherembodiment of the present invention refers to thoses processes whereinwhen the 4 to 10 membered heterocyclic is aromatic, it may be optionallysubstituted by 1 R⁹ substituent.

An embodiment of the present invention refers to thoses processeswherein the 4 to 10 membered heterocyclic group is an aromaticheterocyclic group. Examples of suitable of such aromatic hetercyclicgroups include, pyridinyl pyrimidinyl, pyrazinyl, quinolinyl,isoquinolinyl, pyrrolyl, pyrazoyll, imidazolyl, thiophenyl, furanyyl,indolyl and benzofuranyl.

Another embodiment of the present invention refers to those processeswherein the the 4 to 10 membered hetercyclic group is a non-aromaticheterocyclic group. Examples of suitable non-aromatic heterocyclicgroups include tetrahydrothiopranyl thiomorpholino, dioxanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropytranyl, piperidino,morpholino, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,homopiperidinyl, 3-azabicyco[3.1.0hexanyl, 3-azabicyclo[4.1.0]heptanyl,azabicycto[2.2.2]hexanyl, 3H-indolyl, and 4H-pyranyl.

Another embodiment of the present invention refers to those processeswherein the 4 to 10 membered aromatic heterocyclic group containing oneor more heteroatoms each selected from O, S and N contains one to fourheteroatoms each selected from O, S and N, with the proviso that said 4to 10 membered aromatic heterocyclic does not contain two adjacent O orS atoms, In a preferred embodiment, the 4 to 10 membered hetercyclicgroup contains one to two O atoms, and in another embodiment one O atom.In another embodiment, the 4 to 10 membered hetercylic group containsone to two N atoms, and in a preferred embodiment one N atom.

Another embodiment of the present invention refers to those processeswherein the compound of formula I is selected from the group consistingof1-{2-[5-(3-Morpholin4-yl-propoxy)-benzoimidazol1-yl-quinolin-8-yl-piperidin4-ylamine;

(±)-1-{2-[5-(Tetrahydro-furan-3-3-yloxy)-benzoimidazol-1-quinolin-[-8-yl-}-piperidin-4-ylamine;

(+)-1-{2-[5-(Tetrahydro-furan3-yloxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin4-ylamine;

(−)-1-55 2-[5-(Tetrahydro-furan-3-yloxy)-benzomidazol-1-yl]-quinolin-8-yl}-piperidin4-ylamine;

1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine;

1-{2-[5-(Tetrahdro-pyran-4-yloxy)-benzoimnidazol-1-yl]quinolin8-yl}-piperidin-4-ylarmine;and the pharmaceutically acceptable salts, prodrugs, hydrates andsolvates of the foregoing compounds,

In an especially preferred embodiment, the present invention refers tothose processes wherein the compound of formula I is thebenezenesulfonate salt of1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylamine.

The present invention also relates to a process for preparing a compoundof formula

wherein Bn is benzyl and wherein R¹, R², R³ and R⁴ are as defined abovefor formula I; comprising reacting a compound of formula VII

wherein R³ and R⁴ are as defined above for formula I, with a compound offormula VIII

wherein R¹ and R² are as defined above for formula I, in the presence of1,2-Bis(diphenylphosphino)ethane, a base and a a palladium catalyst,such as a palladium (0) or a palladium (II) catalyst. The palladiumcatalyst is preferably tri(dibenzylidene acetone) dipailadium (0) orpalladium acetate, with the latter being most preferred. Examples ofsuitable bases include potassium phosphate, sodium t-butoxide and cesiumcarbonate. One especially preferred embodiment of the present inventionrefers to those processes wherein the palladium catalyst is palladiumacetate, and the base is cesium carbonate. The reaction is preferablycarried out in the presence of an aromatic solvent, such as toluene, anether, such as dioxane, dimethoxyethane, or tetrahydrofuran, or a polarnitrogen-containing solvent such as dimethylformamide (DMF). Solventmixtures can also be used. The reaction may be carried out at atemperature of of about 90° C. to about 120° C.

An especially preferred embodiment of the present invention refers tothose processes wherein R¹ and R² in the compound of formula VIII areboth hydrogen, and the compound of formula VII is a compound of formulaVIIA

The compound of formula VI is useful as an intermediate toward thepreparation of the compounds of formrula I.

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro andchloro.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties. It is understood that for said alkyl group to include cyclicmoieties it must contain at least three carbon atoms.

The term “cycloalkyl ”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having cyclic(incuding mono or multicyclic) moieties.

The term “alkenyl”, as used herein, unless otherwise indicated, includesalkyl groups, as defined above, having at least one carbon-carbon doublebond.

The term “alkynyl”, as used herein, unless otherwise indicated includesalkyl groups, as defined above, having at least one carbon-carbon triplebond.

The term “alkoxy”, as used herein, unless otherwise indicated, includesalkyl groups wherein alkyl is as defined above.

The term “solvate”, as used herein includes, a compound of the inventionor a salt thereof, that further includes a stoichiometric ornon-stoichiornetric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for topical administration to humans.

The term “hydrate”, as used herein refers to a compound of the inventionor a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

The term “4 to 10 membered heterocyclic”, as used herein, unlessotherwise indicated, includes aromatic and non-aromatic heterocyclicgroups containing one or more heteroatoms each selected from O, S and N,wherein each heterocyclic group has fron 4 to 10 atoms in its ringsystem. Non-aromatic heterocyclic groups include groups having only 4atoms in their ring system, but aromatic heterocyclic groups must haveat least 5 atoms in their ring system. The heterocyclic groups includebenzo-fused ring systems and ring systems substituted with one or moreoxo moieties. An example of a 4 membered heterocyclic group isazetidinyl (derived from azetidine). An example of a 5 memberedheterocyclic group is thiazolyl and an example of a 10 memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl,thietanytl, homopiperdinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyndinyl, 2-pyrrolinyl, 3-pyrroiniyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxoanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinyl, imidazotinyl, imidazolidinyl, 3-azabicylo[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples ofaromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidiny,pyrazilyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinoliny, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazoyl,indolizinyl, phthaelazinyl, pyridazinyl, triazinyl, isoindolyl,pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, beinzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphtilyidinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition including1-oxa-6-aza-spiro2.5]oct-6-yl. The foregoing groups, as derived from thegroups listed above, may be C-attached or N-attached where such ispossible. For instance, a group derived from pyrole may be pyrrol-1-yl(N-attached) or pyrrol3-yl (C-attached). Further, a group derived fromimidazole may be imidazo1-yl (N-attached) or imidazoi-3-yl (C-attached).An example of a heterocyclic group wherein 2 ring carbon atoms aresubstituted with oxo (=O ) moieties is 1,1-dioxo-thiomorpholinyl.

The phrase “pharmraceutically acceptable sat(s), as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of formula I. The compounds of formula Ithat are basic in nature are capable of forming a wide variety of saltswith a rious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds of formula I are those that form non-toxic acid additionsalts, i.e. salts containing pharmacologically acceptable anions, suchas the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, catcium edetate, camsytate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edistyate,estolate, esylate, ethysuccinate, fumarate. gluceptate, gluconate,glutamate, glycollylarsanilate, hexytresorcinate, trydrabamine,hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate,laurate, malate, mateate, mandelate mesylate, methylsulfate, mucate,napsylate, nitrate, oleate, oxalate, pamoate (embonate), pamitate,pantothenate, phospataeldiphosphate, polygalacturonate, saliclate,stearate, subacetate, succinate, tannate, tartrate, teoclate, tosyate,triethiodode, and valerate salts. Since a single compound of the presentinvention may include more than one acidic or basic moieties, thecompounds of the present invention may include mono, di or tri-salts ina single compound.

In general, “prodrugs” of the compounds of the formula I are functionalderivativatives of the compounds of formula I which are readilyconvertible convertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

A prodrug may be a pharmacologically inactive derivative of abiologically active substance (the “parent drug” or “parent molecule”)that requires transformation within the body in order to release theactive drug, and that has improved delivery properties over the parentdrug molecule. The transformation in vivo may be, for example, as theresult of some metabolic process, such as chemical or enzymatichydrolysis of a carboxytic, phosphoric or sulphate ester, or reductionor oxidation of a susceptible functionalty.

Compounds referrred to in the processes of the present invention havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e .g, two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes 4-hydroxyprolilne, hydroxylysine, demosine,isodernosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrutline homocysteine, homoserine, ornithineand methionine sulfone. Additional types of prodrugs are alsoencompassed. For instance, free carboxy groups can be derivatized asamides or alkyl esters. Free hydroxy groups may be derivatized usinggroups including but not limited to hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlinedin “Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs ofhydroxy and amino groups are also included, as are carbonate prodrugs,suffonate esters and sulfate esters of hydroxy groups. Derivatization ofhydroxy groups as (acyloxy)methyl and (acytoxy)ethyl ethers wherein theacyl group may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in J. Med. Chem. 1996, 39, 10. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities.

The compounds referred to in the processes of the present invention mayhave one or more asymmetric centres, and may accordingly exist both asenantiormers and as diastereolsomers. It is to be understood that allsuch isomers and mixtures thereof are encompassed within the scope ofsuch ccmpounds. Certain compounds of formula I may have asymmetriccenters and therefore exist in different enantiomeric forms, All opticalisomers and stereoisomers of the compounds of formula I, and mixturesthereof, are considered to be within the scope of the compounds offormula I. The compounds of formula I may include a racemate, one ormore enantiomeric forms, one or more diastereomeric forms, or mixturesthereof. The compounds of formula I may also exist as tautomers.Reference to the compound of formula I includes reference to the use ofall such tautomers and mixtures thereof.

The term “Me” means methyl, “Et” means ethyl, and “Ac” means acetyl,

The term “DMF”, as used herein, unless otherwise indicated, meansdimethyformamide.

The term “NMP”, as used herein, unless otherwise indicated, meansN-methypyrrolidinone (also known as 1-Methyl-2-pyrrolidinone}.

The acronym “DIPHOS”, as used herein, unless otherwise indicated, refersto 1, 2-Bis(diphenylphosphino)ethane

The term “BINAP[ (abbreviation for2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl), as used herein, unlessotherwise indicated, is represented by the following formula:

The compounds referred to in the processes of the present invention alsoinclude isotopically-labelled compounds, which are identical tocompounds referred to herein, but for the fact that one or more atomsare replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitroen, oxygen, phosphorous,fluorine and chlorine, such as 2H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, and ³⁸Cl, respectively. Compounds referred to in thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of such compounds. Certain isotopically-labelled compoundsreferred to in the present invention, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labelledcompounds of Formula I of this invention and prodrugs thereof cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples and Preparations below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

Each of the patents, patent applications, published Internationalapplications, and scientific publications referred to in this patentapplication is incorporated herein by reference in its entirety.

DETAILED DESCRIPTION OF THE INVENTION

General synthetic methods which may be referred to for preparing thecompounds of formula I are provided in U.S. Pat. No. 5,990,146 (issuedNov. 23, 1999) (Warner-Lambert Co.) and PCT published applicationnumbers WO 99/16755 (published Apr. 8, 1999) (Merck & Co.) and WO01140217 (published Jul. 7, 2001) (Pfizer, Inc.).

Compounds of the formula I may also be prepared according to thefollowing reaction scheme and discussion. Unless otherwise indicated,R¹, R², R³ and R⁴ in the reaction scheme and discussion that follow areas defined above.

With reference to Scheme I above, the compond of formula I may beprepared starting with the palladium amination of reaction of a2chloro-8-benzyloxyquinoline (VIII) and an appropriate2-amino-nitrobenzene (VII) to provide the quinoline (VI). Reduction ofthe nitro group and removal of the benzyl group via cataytichydrogenation, followed by addition of formamidine acetate provides thebenzimidazole (V) which can then be transformed into the correspondingtrifiate (IV). A second palladium catalyzed amination With amine (III)provides piperidinyl quinoline (II) and subsequent removal of thet-butoxycarbonyl group provides (I).

While not wishing to be bound by theory, the presently claimed processfor the preparation of the compounds of formula I from the compounds offormula II under basic (alkaline) conditions is believed to proceedthrough an isocyanate intermediate (IX) that results from thedeprofonation (of the NH proton) of (II) followed by elimination of thet-butoxy group. Hydrolysis of the isocyanate (IX) is believed to producea carbamic acid (X), which undergoes decarboxylation to produce (I).This mechanism is illustrated in Scheme 2 below. The presence of wateras a reactant can be explained by this mechanism.

The reaction of the compound of formula VIII with the compound offormula VII in the presence of palladium acetate and DIPHOS (1,2-Bis(diphenylphosphino)ethane} to produce the compound of formula VI isparticularly and unexpectedly advantageous compared to the same reactionusing palladium acetate, BINAP and PhB(OH)₂. The reaction in thepresence of DIPHOS results in higher (e.g., 5-25% higher) yields of theproduct and takes less time to go to completion, particularly in highscale (e.g., 100 grams and higher) synthesis. This process hassignificant commercial advantages for the production of activeingredients for use in the preparation of a drug.

The starting materials employed in Scheme 1 are readily commerciallyavailable or readily prepared using methods well known to those ofordinary skill in the art.

In each of the reactions discussed or illustrated in the Schemes,pressure is not critical unless otherwise indicated. Pressures fromabout 0.5 atmospheres to about 5 atmospheres are generally acceptable,and ambient pressure i.e., about 1 atmosphere, is preferred as a matterof convenience.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention, methods of preparingsuch compounds, and the methods of the present invention. It is to beunderstood that the scope of the present invention is not limited in anyway by the scope of the following examples and preparations. In thefollowing examples molecules with a single chiral center, unlessotherwise noted, exist as a racemic mixture. Those molecules with two ormore chiral centers, unless otherwise noted, exist as a racemic mixtureof diastereomers. Single enantiomers/diastereomers may be obtained bymethods known to those skilled in the art.

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 mL/minute.

The present invention is illustrated by the following Examples. It willbe understood, however, that the invention is not limited by thespecific details of the following Examples.

EXAMPLE 1

Preparation of 4-(3-Methyl-oxetan-3-ylmethoxy)-2-nitro-phenylamine

The compound, 3-methyl-3-oxetanemethanol (468 g, 45.8 mmoml. 1.05equivalent), acetonitnrle (25 mL, 5 volumes), and triethylamine (6.7 mL,48 mmol, 1.1 equivalent) were charged to a 100 mL round bottomed flaskand then cooled to 5-15° C. Methanesulfonyl chloride (3.4 mL, 43.6 mmol,1.0 equivalent) was charged at a rate which kept the temperature below45° C. The mixture was stirred at 15-20° C. for 2-6 hours, then cooledto 0-5° C. The solids were filtered through a pad of Celite, then theflask and the filter cake were washed once with 10 mL of acetonitrile.Thereafter, 4-amino-nitophenol (6.73 g 43.6 mmol 1 equivalent) andcesium carbonate (18.5 g, 56.7 mmol, 1.3 equivalents) were charged tothe filtrate and the mixture was heated at 45-60° C. for 24 h. Uponreaction completion, ethyl acetate 30 mL, 6 volumes) was charged to theflask. The mixture was stirred for 15-60 min at 35-40° C., and thenfiltered at 35-40° C. through a pad of Celite. The flask and the filtercake were rinsed with 2 by 6 volumes of ethyl acetate. The filtrate wasthen washed with 25 volumes of 0.5 N sodium hydroxide solution, followedby 25 volumes of saturated sodium chloride solution. The resultingsolution was concentrated to low volume and isopropanol (25 mL, 5volumes) was added. The solids were granulated at 20-25° C. for at least10 hours and then collected and dried under vacuum at 40° C. with aslight nitrogen bleed to provide 7.7 g of a reddish orange fluffy solid(74% yield). ¹H NMR (d₆-DMSO): δ 741 (d, 1H, J=2.9 Hz), 7.29 (br s, 2H),7.18 (dd, 1H, J=9.1, 2.9 Hz), 6.98 (d, 1H, J=9.1 Hz), 4.46 (d, 2H, J=5.8Hz), 4.26 (d, 2H, J=5.8 Hz), 3,98 (S, 2H), 1.32 (s, 3H).

EXAMPLE 2

Preparation of(8-Benzyloxy-quinolin-2-yl)-[4-(3-methyl-oxetan-3-ylmethoxy)-2-nitro-phenyl]-amine

The compound, 8-Benzyoxy-quinolin-2-ol (5 g, 18.5 m,mol, 1.0equivalent), 4-(3-Methyl-oxetan-3-ylmethoxy)-2-nitro-phenylamine (5.3 g,22.2 mmol, 1,2 equivalents), cesium carbonate (8.46 g, 26 mmol, 1.4equivalents), DIPHOS (1, 2-Bis(diphenylphosphino)ethane; 443 mg, 111μmol, 0.06 equivalents) and toluene (75 mL, 15 volumes) were charged toa 100 mL round bottom flask. The reaction was deoxygenated. Palladiumacetate (83 mg, 37 μmol, 0.02 equivalents) was added and the reactionwas deoxygenated again. The reaction was heated to 100° C. for 24-30hours. At reaction completion, the reaction was cooled to 55° C. anddichloroethane (“DCE”; 75 mL, 15 volumes) was charged. The slurry wasfiltered through a pad of Celite and then the flask and filter wererinsed once with additional DOCE (50 mL, 10 volumes). The oranics wereconcentrated to low volume and ethyl acetate (50 mL, 10 volumes) wasadded. The reaction was heated to reflux and allowed to cool to 20-25°C. The solids were granulated for 10-20 hours, filtered, and dried undervacuum at 40° C. with a slight nitrogen bleed to yield 6.72 g(8-Benxoxy-quinolin-2-yl)-[4-(3-methy-oxetan3ylmethoxy)-2-nitro-phenyl]-amineas an orange solid (77% yield). The material was judged to be about 95%pure by NMR, with ˜5% of the DIPHOS bis-oxide.

¹H NMR (d₆-DMSO): δ 9.78 (s, 1H), 8.73 (d, 1H, J=9.1 Hz), 8.11 (d, 1H,J=8.7 Hz), 7.55 (m, 2H), 7,36 (m, 4H), 7.22 (m, 4H) 5.20 (s, 2H), 452(d, 2H, J=5.8 Hz), 4.34 (d, 2H, J =5.8 Hz), 4.12 (s, 2H), 1.40 (s, 3H).

EXAMPLE 3

Preparation of2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]quinolin-8ol

phenyl]-amine (5 g, 10.6 mmol, 1,0 equivalent), ethanol (50 mL, 10volumes), triethylamine (7.8 mL, 56.2 mmol, 5.3 equivalents), andpalladium hydroxide on carbon (500 mg, 0.1 weight equivalents) werecharged to a 100 mL round bottom flask. The solution was deoxygenatedand then heated to 50° C. Once the reaction reached 50° C., formic acid(2,2 ml, 56.2 mmol, 5.3 equivalents) was charged slowly to control anyexotherm or off-gasing. The reaction was then heated at 55° C. for 15-25hours. After nitro group reduction and benzyl group removal was noted byAPCI MS, the reaction was cooled to 40° C. and filtered through a pad ofCelite. The flask and the filter cake were washed once with ethanol (2.5volumes). The filtrate was then charged to another 100 mL round bottomflask containing form amdine acetate (2.3 g, 22.3 mmol, 2.1 equivalents)and the reaction was heated at reflux for ˜8 hours. At reactioncompletion, the reaction was cooled to 20-25° C. and allowed togranulate for 10-20 hours. The solids were isolated by filtration anddried under vacuum at 40° C. with a slight nitrogen bleed to afford 3.14g of2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-ol asa yellow solid (82% yield). ¹H NMR {d₆-DMSO): δ 9.88 (s, 1H), 9.25 (s,1H), 8.61 (d, 1H, J=9.1 Hz), 8.51 (d, 1H, J=9,1 Hz), 8.10 (d, 1H, J=9.1Hz), 7.44 (m, 2H). 7.35 (d, 1H, J=2.5 Hz), 7.18 (dd, 1H, J=7.5, 1.7 Hz),7.08(dd, 1H, J=8.7, 2.5Hz), 4.51 (d, 2H, J=5.38 Hz),4.31 (d, 2H, J=5.8Hz), 4.12 (s, 2H), 1.39 (s, 3H).

EXAMPLE4

Preparation of Trifluoro-methanesulfonic acid2-[5-(3-methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-ylester

N-Phenyftrifluoromethanesulfonimide (PhN(Tf)₂, 2.72 g, 7.6 mmol, 1.1equivalents),2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-)quinolin-8-ol(2.5 g, 6.9 mmol, 1.0 equivalent), DMF (7.5 mL, 3 volumes), and thentriethylamine (1.9 mL, 13.8 mmol, 2.0 equivalents) were charged to a 50mL round bottom flask. The slurry was stirred at 20-30° C. for 20-10hours. After the stirring period, the reaction was filtered and washedwith DMF (2.5 mL, 1 volume), followed by isopropy ether (5 mL, 2volumes) to yield, after drying under vacuum at 40° C. with a slightnitrogen bleed, 2.9 g trifluoro-methanesulfonic acid2-[5-(3-methy-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]quinolin-8-yl esteras an off-white solid (85% yield).

¹H NMR (4₈-DMSO): δ 9,18 (s 1H), 8.75 (d, 1H, J=9.1 Hz), 8.65 (d, 1H,J=8.7 Hz), 8.33 (d, 1H, J=9.1 Hz), 8.18 (dd, 1H, J=8.3, 1.2 Hz), 7.94(d, 1H, J=8.9 Hz), 7.70 (t, 1H, J=7.9 Hz), 7.36 (d, 1H, J=2.1 Hz), 7.02(dd 1H, J=9.1, 2.5 Hz), 4.51 (d, 2H, J=5.8 Hz), 4.31 (d 2H, 4=J5.8 Hz),4.12 (s, 2H), 1.39 (s, 3H).

EXAMPLE 5

Preparation of(1-(2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4)-carbamicacid tert-butyl ester

BiNAP (379 mg, 608 μmol, 0.06 equivalents),tris{dibenzyideneacetone)dipalladium (186 mg, 203 μmol, 0.02equivalents) and toluene (35 mL, 7 volumes) were added to a 100 mL roundbottom flask. The solution was dieoxygenated and stirred at 20-25° C.for ˜30 minutes. Next, trlfluoro-methanesulfonic acid2-[-(3-methyxl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl}-quinolin-8-ylester (5 g, 10.1 mmol, 1 equivalent), piperidin-4yl-carbamic acidtert-butyl ester (4.06 g 20.3 mmol, 2.0 equivalents), and cesiumcarbonate (4.62 g 1.42 mmol, 1.3 equivalents) were charged. The reactionwas again deoxygenated and then heated to 85° C. for 24-32 hours. Atreaction completion, the reaction was cooled to 30° C. anddichloroethane (5 volumes) and Celite (0.5 wt. equivalent) were added.The slurry was filtered through a pad of Celite and rinsed withdichloroethane (5 volumes). The mother liquor was then concentrated tolow volume and ethyl acetate (75 mL, 15 volumes) was charged. The thinslurry was granulated at 20-25° C. for 8-15 h and then filtered. Themother liquor was collected and washed with a 2.5% NaH₂PO₄ solution (3×9volumes). The organics were again concentrated to low volume andacetonitrile (25 mL, 5 volumes) was charged. The slurry was granulatedfor 10-20 hours, and then the solids were filtered and dried undervacuum at 40° C. wth a slight nitrogen bleed to yield 4.33 g(1-(2-[5-(3-Methyl-oxetan-3-ylmethoxy)benzoimidazol-1-yl-quinolin-8-yl,-piperidin4-yl)-carbamicacid tert-butyl ester as a yellow solid (79% yield).

¹H NMR (d₆-DMSO) δ 9.17 (s, 1H), 8.89 (d, 1H, J=8.7 Hz), 8.51 (d, 1H,J=9.1 Hz), 8.15 (d, 1H, J=9.1 Hz), 7.59 (d, 1, J=8.3 Hz), 7.47 (t, 1H,J=7.9 Hz), 7.35 (m 2H), 7,29 (m, 1H), 7.14 (d, 1H, J=8.3 Hz), 4.54 (d,2H, J=5.4 Hz), 4.32 (d, 2H, J=5.8 Hz), 4.13 (s, 2HR) 3.75 (d, 2H, J=11.6Hz), 3.45 (m, 1H), 2.75 (m, 2H), 1.84 (m, 4H), 1.40 (s, 3H), 1.39 (s,9H).

EXAMPLE 6

Preparation of1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazzol-1-yl)-quinolin-8-yl}-piperidin-4-ylamine

The comnpound,(1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin8-yl}-piperidin-4-l)-carbamic acid tert-butyt ester (2 g, 3.68 mmol, 1equivalent), sodium t-butoxide (1.77 g, 18.4 mmol, 5 equivalents),2-methyltetrahydrofuran (30 mL, 15 volumes), and water (66 mL, 1equivalent) were added to a 100 mL round bottom flask. The mixture washeated to reflux and held at reflux for 24-30 hours. At reactioncompletion, the mixture was cooled to 20-30° C., The reaction wasquenched into a 20% citric acid solution (10 volumes) and stirred at20-30° C. for 30-60 minutes. The citrate salt precipitated out ofsolution during this time. A 50% sodium hydroxide solution (˜1 weightequivalent) was charged to basify the reaction mixture (pH 10-12). Thelayers were separated at 30-40° C. The aqueous layer was washed withethyl acetate (10 volumes) and then the combined organic wereconcentrated to low volume. Ethyl acetate (14 mL, 7 volumes) was chargedand the slurry was allowed to granulate for 10-20 hours. The solids werefiltered and 1-(2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]quinolin-8-yl)piperidin-4-ylamine(1. 4 g 86% yield) was isolated.

¹H NMR (d₆-DMSO): δ 9.17 (s, 1H), 8.88 (d. 1H, J=8.7 Hz), 8.51 (d, 1HJ=9.1 Hz), 8.14 (d, 1H, J=9.1 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.46 (t 1H,J=7.9 Hz), 7.37 (d, 1H, J=2.5 Hz), 7.26 (d, 1H, J=7.9 Hz), 7.15 (dd1H_(J=)9.1, 2.5 Hz), 4.53 (,d, 2H, J=5.8 Hz), 4.31 (d, 2H, J=5.8 Hz),4.13 (s, 2H), 3.71 (d, 2H, J=10.4 Hz), 2.73 (m, 3H), 1.87 (d, 2H, J=11.4Hz), 1.77 (m, 2H), 1.39 (s, 3H).

EXAMPLE 7

Preparation of1-{2-[5-(3-Methyl-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl}-piperidin-4-ylaminebenzensulfonate

The compound,1-2-[5-(3-Methoxy-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-yl)-piperidin-4-ylamine(2.44 g, 5.5 mmnol, 1 equivalent) and ethanol (24 mL, 10 volumes) wereadded to a 100 mL round bottom flask. The solution was heated to refluxto dissolve the starting material and then cooled to room temperature. Asolution of benzenesulfonic acid (918 mg, 5.2 mmol, 0.95 equivalents) inethanol (5 mL, 2 volumes) was charged and the reaction was heated torefliux for ˜30 minutes. The reaction was cooled to 20-30° C. andallowed to granulate for 16-32 hours. The material was then filtered anddried under vacuum with a slight nitrogen bleed to afford1-{2-[5-(3-Methy-oxetan-3-ylmethoxy)-benzoimidazol-1-yl]-quinolin-8-)}-piperidin-4-ylaminebenzenesulfonate (2.8 g, 85% yield) as an off-white solid,

¹H NMR (d₆-DMSO): δ 9.19 (s, 1H), 8.87 (d, 1H, J=9.1 Hz), 8.54 (d, 1H,J=9.1 Hz), 8.16 (d 1H, J=9.1 Hz), 7.94 (br S, 3H), 7.63 (d, 1H J=75 Hz),7.56 (m 2H), 7.48 (t, 1H, J=7.9 Hz), 7.39 (d 1H, J=2.5 Hz), 7.26 (m,5H), 4.53 (d, 2H, J=5.8 Hz), 4.31 (d, 2H, J=5.8 Hz), 4.12 (s, 2H), 3.83(m, 2H), 3.2 (m, 1H), 2.78 (m, 2H), 2.05 (m, 2H), 1.95 (m, 2H), 1.39 (s,3H).

1.-40. (canceled)
 41. A process for preparing a compound of formula VI

wherein Bn is benzyi;. wherein each R¹, R², and R³ is independentlyselected from the group consisting of H, (C₁-C₆)alkyl, C₃-C₆)cycloalkyl,halo, cyano, CF₃, difluoromethoxy, trituoromethoxy, —O(C₁-C₆)alkyl,—O(C₃-C₆)cycloalkyl, and —NR¹²R¹³; wherein R⁴ is —(CR⁵R⁶)_(m)H or—(CR⁷R⁸)_(n)(4 to 10membered)-aromatic or non-aromatic heterocyclic,wherein m is an integer rangng from 1 to 5, wherein n is an integerranging from 0 to 5 wherein said 4 to 10 membered heterocyclic whenaromatic is optionally substituted by 1 to 3 R¹¹ substituents, andwherein said 4 to 10 membered heterocyclic wnen non-aromatic isopotionally substituted by 1 to 3 R¹⁰ substituents at any position andoptionally subtstituted by 1 to 3 R¹¹ substituents at any position notadacent to or directly attached to a heteroatom; wherein each R⁵, R⁶, R⁷and R⁸ is independently selected froml the group consisting of H and(C₁-C₆)alkyl; wherein each R⁹ is independently selected from H,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, halo, cyano, CF₃, difluoromethoxy,trifluoromethoxy, —O(C₁-C₆)alkyl, —O(C₁-C₆)cycloalkyl, and —NR¹⁴R¹⁵;wherein each R¹⁰ is independently selected from H, (C₁-C₆)alkyl, and(C₃-C₆)cycloalkyl; wherein each R¹¹ is independently selected from halo,cyano, CF₃, difluoromethoxy, trifluoromethoxy; —O(C₁-C₆)alkyl,—O(C₃-C₆)cycloalkyl, and —NR¹⁶R¹⁷; wherein R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ andR¹⁷ are independently selected from the group consisting of H,(C₁-C₆)alkyl, and (C₃-C₆)cycloalkyl; wherein each of the aforesaid(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, —O(C₁-C₆)alkyl and —O(C₃-C₆)cycloalkylsubstituents wherever they occur may optionally be independentlysubstituted by one to three substituents independently selected from thegroup consisting of halo cyano, amino, (C₁-C₆)akylamino,[(C₁-C₆)alkyl]₂-amino, perhalo(C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, and (C₁-C₆)alkoxy; comprisingreacting a compound of formula VII

wherein R³ and R⁴ are as defined above for formula VI, with a compoundof formula VIII

wherein R¹ and R² are as defined above for formula VI, in the presenceof 1, 2-Bis(diphenylphosphino)ethane, a palladiun catalyst and a base.42. A process according to claim 41, wherein the palladium catalyst ispalladium acetate.
 43. A process according to claim 41, wherein thepalladium catalyst is tris(dibenzylidene acetone) dipalladium (0).
 44. Aprocess according to claim 42, wherein the base is cesiuim carbonate.45. A process according to claim 42, wherein each R¹, R², and R³ isindependently selected from H, (C₁-C₆)alkyl, and (C₃-C₆)cycloalkyl,halo, and cyano.
 46. A process according to claim 44, wherein R⁴ is—(CR⁷R⁸)_(n)(4 to 10 membered)-non-aromatic heterocyclic, wherein n isan integer from 0 to 1 and wherein said 4 to 10 membered nonaromaticheterocyclic group is optionally substituted by 1 to 3 R¹⁰ substituents.47. A process according to claim 46, wherein said 4 to 10 memberednon-aromatic heterocyclic is selected from the group consisting oftetrahydrofuranyl, morpholino and oxetanyl.
 48. A process according toclaim 47, wherein said 4 to 10 membered non-aromatic heterocyclic isoxetanyl.
 49. A process according to claim 41, wherein R¹ and R² areboth hydrogen, and the compound of formula VII is a compound of formulaVIIA.


50. A process according to claim 41, wherein the reaction is performedin the presence of an aromatic solvent, an ether or a mixture thereof.51. A process according to claim 50, wherein the reaction is performedin the presence of an aromatic solvent.
 52. A process according toclaimn 51, wherein the aromatic solvent is toluene.
 53. A processaccording to claim 41, wherein the reaction is performed at atemperature of ahout 90° C. to about 120° C.
 54. A process according toclaim 50, wherein the ether is at least one member selected from thegroup consisting of tetrahydrofuran, dimethoxyethane, dimethylformamideand dioxane.